The aim of this application is to produce pilot-scale libraries for evaluation via the Molecular Library Screening Network (MLSCN). It is expected that the output from MLSCN screening of these "designer collections" will help enable the promise of chemical biology, unearthing quality small molecule probes to elucidate physiological roles of proteins of unknown function. 25 libraries will be targeted, comprising 25-80 characterized compounds (>10mg, >90% pure). To this end, effective file enhancement requires complementary skill sets in multiple functional areas and as such, the collective investigators have proposed a multitude of potentially robust medicinally relevant protocols and possess a depth of expertise in high-throughput medicinal chemistry and drug design principles spanning both academic and industrial settings. The combined infrastructures of the collaborative parties further strengthen this application, with ready access to state of the art screening, structural biology, high-throughput instrumentation and core chemistry facilities. The notion of scaffold uniqueness will be evaluated using measurements of molecular dissimilarity based on observed substructure patterns and their frequency of occurrence in PubChem and vendor databases. Evaluation tools will include but are not limited to standard diverse subset and hierarchical chemotype-based analyses. Selected scaffolds will also have a strong biological rational, often taking advantage of crucial molecular recognition motifs of multiple target families. All scaffolds are unique and viewed as structurally compelling. Resupply and future SAR studies will be facilitated by selection of scaffolds possessing 'High Iterative Efficiency Potential'that 1) improve the iterative speed of the medicinal chemist navigating the 'hypothesis-synthesis-screening'loop and 2) reduce the number of required iterations for milestone progression. Designer libraries detailed herein will be presenting opportunities for therapeutic advances in multiple indications. PUBLIC HEALTH RELEVANCE: An immense opportunity has been created to improve human health and longevity. Roles of a plethora of new macromolecules in disease progression may now be investigated by preparation of collections of potential molecular probes detailed herein. Once identified, these small molecules may ultimately be the precursors to disease modifying drugs that address currently unmet medical needs.